The present invention concerns the use of epidermal growth factor (EGF) and fibroblast growth factor (FGF) in methods for preventing tissue damage in a patient after the tissue has been deprived of its blood supply, for example as occurs after an ischemic episode.
Many tissues of the body are highly susceptible to tissue damage or death following a period of inadequate oxygen and nutrient supply, as occurs when there is an insufficiency of arterial blood supply or venous drainage. In such cases, an infarct may develop in the tissue, which is an area of necrosis resulting from the sudden reduction of the blood supply. A reduction in the blood supply to a tissue may be caused by blockage of a vein or artery servicing that tissue. Such a blockage of the blood supply may be caused by emboli or thrombi (types of blood vessel clots), vascular torsion or pressure that produces a macroscopic area of necrosis. Tissues that are likely to be affected by a reduction of blood supply and oxygen are central nervous system (CNS), myocardial, renal, spleen, intestinal and lung tissues.
A sudden reduction in the blood supply to a tissue is generally referred to as an ischemic event and as used herein the term "ischemic" shall mean a local anemia due to an obstruction (of any type) of the blood supply to that tissue (usually by arterial narrowing). Common examples of this type of problem are myocardial ischemia, which is the inadequate circulation of blood to myocardium, usually as a result of coronary artery disease; myocardial infarction, which is an infarction of an area of the heart muscle usually as a result of occlusion of a coronary artery; and cerebral ischemia or stroke, which is a neurological affliction resulting from the sudden reduction in cerebral blood supply. The term "stroke" (sometimes called apoplexy) is a lay term which refers to the sudden diminution or loss of consciousness, sensation and voluntary motion caused by rupture or obstruction of an artery of the brain. Stroke is usually more specifically described by the nature of the underlying disturbance, e.g. thrombosis, hemorrhage or embolism.
Cerebral ischemia may be distiguished from hypoxia, which is the interference with the oxygen supply to the brain despite a relatively normal cerebral blood flow and normal perfusion pressure. Cerebral hypoxia occurs for a variety of reasons, including a general reduction of atmospheric oxygen tension, pollution of the atmosphere (e.g., by carbon monoxide), chronic Pulmonary disease, pulmonary emboli and reduced or altered oxygen-carrying capability of the blood (e.g., anemia). Ischemic infarction will occur as a consequence of severe hypoxia.
There are various degrees of cerebral ischemia. A transient ischemic attack (TIA) is defined as a loss of neurologic function caused by ischemia, abrupt in onset, persisting for less than twenty-four hours, and clearing without residual signs. Most such TIA's last only a few minutes. If disability persists for more than twenty-four hours, but is attended ultimately by no persisting symptoms or signs, it is conventionally called a reversible ischemic neurologic disability (RIND). An ischemic event that is sufficiently severe and in an appropriate location to leave persistent disability but is short of a calamatous stroke, is defined as a partial nonprogressing stroke (PNS). The ultimate in severity of ischemia produces a more major degree of permanent neurologic disability, sometimes referred to as a completed stroke. In those cases where the ischemia has been prolonged, neuronal cell death occurs. The brain softens and the margins between the gray and white matter become indistinct. Under the microscope the neurons (if still present) may be observed to be shrunken and pyknotic. These lesions result in permanent neurologic disability.
Present therapies for treating or preventing ischemic events, such as cerebral stroke, include risk factor management, anti-spasmodic drugs, anti-thrombotic drugs and surgery. These therapies have disadvantages and are not always successful. Therefore, the medical community is in need of a better method for treating or preventing ischemic events. The present invention provides such methods by use of EGF and FGF to treat the damaged tissue. At the present time, there are no clinically useful methods for the direct protection of neurons and/or glia cells (aka neuroglia cells, which are non-neuronal cellular elements of the central and peripheral nervous systems) following cerebral ischemia and the present invention provides such methods.
To date, nerve growth factor (NGF) is the most well known polypeptide cell growth factor whose presence has been demonstrated to be unequivocally required for maintenance and maturation of neuronal cells. Most of the other polypeptide cell growth factors do not have the same effect on neuronal cells. For instance, in the past, EGF has not been shown to have an effect on neuronal growth and it does not bear any structural similarity to NGF.
Furthermore, there is no sequence homology between NGF and EGF and neither growth factor can compete with the homologous ligand-receptor interaction of the other growth factor.
Fibroblast growth factor, on the other hand, is known to be neurotrophic (i.e., stimulates the growth of neuronal cells). For example, see Unsicker, K. et al., Proc. Natl. Acad. Sci. USA 84:5459-5463 (August 1987); Gensburger, C. et al., FEBS Lett. 217:1-5 (June 1987); Siebers, J. et al., Neuroscience Letters 76:157-162 (1987); and Morrison, R.S., J. Neurosci. Res. 17:99-101 (1987). Also, FGF has been described as useful to treat heart disease. See, U.S. Pat. Nos. 4,296,100 and 4,378,347 which both describe the use of fibroblast growth factor in the treatment of ischemic heart disease and myocardial infarction. In a recent publication, Anderson et al. (Nature 332:360-361 (March 24, 1988)) describe that FGF may be beneficial in the treatment of Alzheimer's disease as well as treatment of other neurodegenerative disorders of the CNS involving loss of non-cholinerigic neurons such as stroke, epilepsy or ischemia. In spite of the known neurotrophic nature of FGF, prior to the present invention, no one has suggested its use to prevent tissue damage after an ischemic event has occurred.